WO2017173395A1 - Méthodes de traitement de l'hypophosphatasie chez les adolescents et les adultes - Google Patents

Méthodes de traitement de l'hypophosphatasie chez les adolescents et les adultes Download PDF

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WO2017173395A1
WO2017173395A1 PCT/US2017/025590 US2017025590W WO2017173395A1 WO 2017173395 A1 WO2017173395 A1 WO 2017173395A1 US 2017025590 W US2017025590 W US 2017025590W WO 2017173395 A1 WO2017173395 A1 WO 2017173395A1
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years
salp
hpp
patient
age
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PCT/US2017/025590
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English (en)
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Kenji Fujita
Dawn PHILLIPS
Agustin MELIAN
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Alexion Pharmaceuticals, Inc.
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Priority to US16/087,180 priority Critical patent/US10898549B2/en
Priority to EP17776867.8A priority patent/EP3436020A4/fr
Publication of WO2017173395A1 publication Critical patent/WO2017173395A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03001—Alkaline phosphatase (3.1.3.1)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the disclosure relates to methods for treating hypophosphatasia (HPP).
  • HPP hypophosphatasia
  • HPP Hypophosphatasia
  • TAALP tissue-nonspecific alkaline phosphatase
  • HPP Most patients having HPP display skeletal changes, short stature, painful lower limbs, gait disturbance, and premature shedding of teeth.
  • symptoms of HPP can include rickets (osteomalacia); short stature; skeletal deformities, such as bowed legs and enlarged wrists, knees, and ankles as a result of flared metaphyses; and the premature loss of deciduous teeth due to aplasia, hypoplasia, or dysplasia of dental cementum that connects the tooth root with the periodontal ligament.
  • rickets osteomalacia
  • short stature skeletal deformities, such as bowed legs and enlarged wrists, knees, and ankles as a result of flared metaphyses
  • the premature loss of deciduous teeth due to aplasia, hypoplasia, or dysplasia of dental cementum that connects the tooth root with the periodontal ligament.
  • adults having HPP usually present symptoms during middle age, although frequently there is a history of
  • Recurrent metatarsal stress fractures are common and calcium pyrophosphate dihydrate deposition can cause arthritis and pyrophosphate arthropathy in adults having HPP. Due to physical impairments associated with HPP, adolescent and adult patients afflicted with HPP often exhibit decreased walking ability relative to healthy subjects.
  • HPP adolescents having hypophosphatasia
  • sALP soluble alkaline phosphatase
  • Exemplary metrics useful for evaluating the need for or the efficacy of treatment using a sALP include (1 ) the Bruininks-Oseretsky Test of Motor Proficiency 2 nd Edition (BOT-2), (2) the Six Minute Walk Test (6MWT), and (3) plasma PPi and PLP concentrations.
  • the methods further include the use of one or more of the described metrics (e.g., the BOT-2, 6MWT, or plasma PPi and PLP concentrations) singly or in combination to assess treatment efficacy using a sALP for a patient having HPP in which improvements relative to a certain score or value demonstrate that the sALP is effective for treating HPP.
  • methods further include changing the dosage and/or frequency of sALP (e.g., SEQ ID NO: 1 ) administration in order to determine the effective amount of the sALP to administer to an adolescent having HPP or adult having HPP.
  • sALP e.g., SEQ ID NO: 1
  • a first aspect features a method of treating HPP in a patient of about 12 years of age or older than about 12 years of age, which includes administering a sALP to the patient at a dosage providing about 6 mg/kg/week of the sALP.
  • the sALP includes an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 (e.g., asfotase alfa).
  • sALP e.g., SEQ ID NO: 1
  • an adolescent having HPP of about 12 to about 18 years of age or an adult older than about 18 years of age treated with a sALP e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age
  • an average decrease in PPi concentrations in a plasma sample from the patient that is sustained during a treatment period of at least one year relative to PPi concentrations in a plasma sample from an untreated subject having HPP e.g., an average decrease in PLP concentrations in a plasma sample from the patient that is sustained during a treatment period of at least one year relative to PPi concentrations in a plasma sample from an untreated subject having HPP
  • administration of the sALP results in an average increase in a 6MWT value of the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age) relative to the 6MWT value of the patient prior to administration of the sALP.
  • the average increase in the 6MWT value is to about 80% or greater of the predicted 6MWT value of the patient, in which the 6MWT value of the patient was less than about 80% of the predicted 6MWT value of the patient prior to administration of the sALP.
  • the average increase in the 6MWT value of the patient is sustained during a treatment period of at least two years, at least three years, at least four years, or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • the patient also exhibits decreased reliance on an assistive device (e.g., a wheelchair, braces, crutches, or an orthotic) for mobility after administration of the sALP.
  • the average decrease in PPi concentrations in a plasma sample from the patient is about 25% or greater (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more than 60%) relative to PPi concentrations in a plasma sample from the patient prior to administration of the sALP (e.g., SEQ ID NO: 1 ).
  • the average decrease in PPi concentrations in a plasma sample from the patient having HPP is determined relative to PPi concentrations in a plasma sample from an untreated subject having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult older than about 18 years of age).
  • the average decrease in PPi concentrations in a plasma sample from the patient is sustained during a treatment period of at least two years, at least three years, at least four years, or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • the average decrease in PLP concentrations in a plasma sample from the patient is about 50% or greater (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%) relative to PLP concentrations in a plasma sample from the patient prior to administration of the sALP (e.g., SEQ ID NO: 1 ).
  • the average decrease in PLP is about 50% or greater (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%) relative to PLP concentrations in a plasma sample from the patient prior to administration of the sALP (e.g., SEQ ID NO: 1 ).
  • the average decrease in PLP e.g., SEQ ID NO: 1
  • concentrations in a plasma sample from the patient is determined relative to PLP concentrations in a plasma sample from an untreated subject having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age). Additionally, the average decrease in PLP concentrations in a plasma sample from the patient is sustained during a treatment period of at least two years, at least three years, at least four years or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • a second aspect features a method of treating HPP in a patient of about 12 years of age or older than about 12 years of age having a medial total BOT-2 running speed and agility score of less than about 7.
  • the method includes administering a sALP (e.g., SEQ ID NO: 1 ) to the patient (e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age) at a dosage providing about 6 mg/kg/week of the sALP.
  • the sALP includes an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 .
  • Administration of the sALP results in an average increase in the BOT-2 running speed and agility medial total score to about 9 or greater than about 9 that is sustained during a treatment period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient.
  • the medial total BOT-2 running speed and agility score of the patient e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult older than about 18 years of age treated with a sALP
  • a BOT-2 running speed and agility medial total score of an untreated subject having HPP e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult older than about 18 years of age.
  • the average increase in the BOT-2 running speed and agility medial total score is sustained during a treatment period of at least two years, at least three years, at least four years, or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • the medial total BOT-2 running speed and agility score of the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age treated with a sALP) is determined from measurements selected from the group consisting of stepping over a balance beam, shuttle run, two-legged side hop, and one-legged side hop.
  • a third aspect features a method of treating HPP in a patient of about 12 years of age or greater than about 13 years of age having a medial total BOT-2 strength score of less than about 14, in which the method includes administering a sALP to the patient at a dosage providing about 6 mg/kg/week of the sALP.
  • the sALP includes an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 .
  • Administration of the sALP results in an average increase in the BOT-2 strength medial total score to about 18 or greater than about 18.
  • the medial total BOT-2 strength score of the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age treated with a sALP) is determined relative to a BOT-2 strength medial total score of an untreated subject (e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age).
  • the medial total BOT-2 strength score of the patient is determined relative to a BOT-2 strength score of an untreated subject having HPP.
  • the medial total BOT-2 strength score of the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult older than about 18 years of age) is determined from measurements selected from the group consisting of sit-ups, V-ups, standing long jump, wall sit, and push-ups.
  • the patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • the patient is about 12 years of age, older than about 12 years of age, about 1 8 years of age, or older than about 18 years of age.
  • the patient may be one that has not been previously administered the sALP (e.g., SEQ ID NO: 1 ).
  • the sALP (e.g., SEQ ID NO: 1 ) is formulated for daily or weekly administration, such as twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week.
  • the sALP (e.g., SEQ ID NO: 1 ) is formulated at a dosage of 2 mg/kg for administration three times a week, a dosage of 3 mg/kg for administration three times a week, or a dosage of 1 mg/kg for administration six times a week.
  • the sALP (e.g., SEQ ID NO: 1 ) is formulated for administration once daily and/or is formulated for administration on consecutive or alternating days.
  • the sALP (e.g., SEQ ID NO: 1 ) is administered for a treatment period of at least four, least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer, such as for the lifetime of the patient).
  • the sALP (e.g., SEQ ID NO: 1 ) includes or consists of the amino acid sequence of SEQ ID NO: 1 .
  • the sALP (e.g., SEQ ID NO: 1 ) is administered in an amount that is therapeutically effective to treat at least one symptom of HPP (e.g., one or more of rickets, premature loss of deciduous teeth, incomplete bone mineralization, elevated blood and/or urine levels of phosphoethanolamine (PEA), hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture, HPP-related seizure, inadequate weight gain, and calcium pyrophosphate dihydrate crystal deposition).
  • HPP phosphoethanolamine
  • the sALP (e.g., SEQ ID NO: 1 ) is administered at an initial dosage of about 2.1 mg/kg/week or about 3.5 mg/kg/week and then is increased to a dosage of about 6 mg/kg/week or more (e.g., about 9 mg/kg/week).
  • the dosage is increased to a dosage of about 6 mg/kg/week or more after administration of the sALP (e.g., SEQ ID NO: 1 ) for at least six months, at least one year, at least two years, at least three years, at least four years, or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the patient).
  • the sALP e.g., SEQ ID NO: 1
  • symptoms of HPP e.g., rickets, premature loss of deciduous teeth, incomplete bone mineralization, elevated blood and/or urine levels of phosphoethanolamine (PEA), hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture, HPP-related seizure, inadequate weight gain, craniosynostosis, and/or calcium
  • HPP e.g., rickets, premature loss of deciduous teeth, incomplete bone mineralization, elevated blood and/or urine levels of phosphoethanolamine (PEA), hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture, HPP-related seizure, inadequate weight gain, craniosynostosis, and/or calcium
  • pyrophosphate dihydrate crystal deposition presented at birth or did not present at birth.
  • symptoms of HPP presented in the HPP patient at 12 years of age or older (e.g., 13 years of age, 14 years of age, 15 years of age, 1 6 years of age, 17 years of age, 18 years of age, or older).
  • the patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • sALP e.g., SEQ ID NO: 1
  • administration of the sALP such as a lack of or decreased incidence of adverse events selected from the group consisting of injection site erythema, decrease in hemoglobin, pyrexia, pneumonia, upper respiratory tract infection, otitis media, vomiting, constipation, diarrhea, tooth loss, nasopharyngitis, rash, dental carries, and irritability.
  • the sALP (e.g., SEQ ID NO: 1 ) is formulated in a pharmaceutical composition, with at least one pharmaceutically acceptable carrier, such as saline (e.g., sodium chloride and sodium phosphate).
  • at least one pharmaceutically acceptable carrier such as saline (e.g., sodium chloride and sodium phosphate).
  • the at least one pharmaceutically acceptable carrier includes 150 mM sodium chloride and 25 mM sodium phosphate.
  • the pharmaceutical composition is formulated for subcutaneous, intramuscular, intravenous, oral, nasal, sublingual, intrathecal, or intradermal administration.
  • the pharmaceutical composition is formulated for subcutaneous administration.
  • the sALP (e.g., SEQ ID NO: 1 ) is physiologically active toward PEA, PPi, and PLP, catalytically competent to improve skeletal mineralization in bone, and/or is the soluble extracellular domain of an alkaline phosphatase.
  • At least refers to an amount that is ⁇ 10% of the recited value and is preferably ⁇ 5 % of the recited value, or more preferably ⁇ 2 % of the recited value.
  • asfotase alfa is meant a human TNALP (hTNALP) fusion protein formulated for the treatment of HPP.
  • Asfotase alfa (STRENSIQ®, Alexion Pharmaceuticals, Inc.) is a fusion protein including a soluble glycoprotein of two identical polypeptide chains, in which each polypeptide chain includes amino acid residues 1 -726 of SEQ ID NO: 1 .
  • the structure of each polypeptide chain includes the catalytic domain of hTNALP, the human immunoglobulin Gi Fc domain, and a deca-aspartate peptide used as a bone targeting domain (the structure hTNALP-Fc-Dio>.
  • the two polypeptide chains are covalently linked by two disulfide bonds.
  • Asfotase alfa has been approved under the trade name STRENSIQ® in the United States, Europe, Japan, Canada, Israel, Australia, and Korea.
  • "average” refers to a numerical value expressing the mean or median of a data set.
  • the mean of a data set is calculated by dividing the sum of the values in the set by their number.
  • the median of a date set is calculated by determining the middle value in a list of odd numbers or by determining the mean of the two data values in the middle in a list of even numbers.
  • bone-targeting moiety refers to an amino acid sequence of between 1 and 50 amino acid residues (such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 22, 24, 25, 26, 28, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 amino acid residues) in length having a sufficient affinity to the bone matrix, such that the bone-targeting moiety, singularly, has an in vivo binding affinity to the bone matrix that is about 10 6 M to about 10 15 M (e.g., 10 7 M, 10 8 M, 10 9 M, 10 10 M, 1 0 1 1 M, 1 0 12 M, 10 13 M, 10 14 M, or 10 15 M).
  • D aspartate
  • E glutamate residues
  • BOT-2 Bruininks-Oseretsky Test of Motor Proficiency 2 nd Edition
  • BOT-2 refers to the second edition of a standardized test of gross and fine motor performance for patients, e.g., including adolescent and adult patients having HPP. See Bruininks, R. H. (2005). Bruininks-Oseretsky Test of Motor Proficiency, (BOT-2). Minneapolis, MN: Pearson Assessment, hereby incorporated by reference in its entirety.
  • the BOT-2 is administered individually to assess gross and fine motor skills of a range of patients.
  • the BOT-2 for example, can be used to evaluate physical impairments and mobility restrictions in patients having HPP (e.g., adults and adolescents having HPP).
  • the BOT-2 provides composite BOT-2 scores in the following exemplary areas: strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination.
  • a BOT-2 strength total score can be determined by having a patient perform sit-ups, v-ups, standing long jump, wall sit, and push-ups.
  • a running speed and agility total score can be determined by having a patient step over a balance beam or perform a shuttle run, two-legged side hop, or one-legged side hop.
  • Both BOT-2 total strength and BOT-2 running speed and agility total scores range from 0 to 25, in which a score of about 10 to 25 is considered representative of healthy subjects.
  • Normative scores for the strength and running speed and agility are 15 +/- 5.
  • Adult and adolescent scores are not normed (does not use the scaled score), and thus higher point values represent better performance.
  • Either average or median scores may be used, with median scores preferred for smaller sample sizes or smaller data sets.
  • catalytically competent refers to a sALP that hydrolyzes the bone mineralization inhibitor inorganic pyrophosphate (PPi) to provide inorganic phosphate (Pi), thereby decreasing the extracellular concentrations of PPi.
  • PPi bone mineralization inhibitor inorganic pyrophosphate
  • the catalytically competent sALP improves skeletal mineralization in bone by regulating the concentration of PPi.
  • extracellular domain is meant any functional extracellular portion of the native protein, e.g., alkaline phosphatase.
  • the extracellular domain lacks the signal peptide.
  • Fc is meant a fragment crystallizable region of an immunoglobulin, e.g., lgG-1 , lgG-2, lgG-3, lgG-3 or lgG-4, including the CH2 and CH3 domains of the immunoglobulin heavy chain. Fc may also include any portion of the hinge region joining the Fab and Fc regions.
  • the Fc can be of any mammal, including human, and may be post-translationally modified (e.g., by glycosylation). In a non-limiting example, Fc can be the fragment crystallizable region of human lgG-1 having the amino acid sequence of SEQ ID NO: 20.
  • fragment is meant a portion of a polypeptide or nucleic acid molecule that contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more of the entire length of the reference nucleic acid molecule or polypeptide.
  • a fragment may contain, e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 1 00, 1 10, 120, 130, 140, 150, 160, 1 70, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 400, 500, 600, 700, or more amino acid residues, up to the entire length of the polypeptide.
  • Exemplary sALP fragments have amino acid residues 18-498, 18-499, 18-500, 18-501 , 18-502, 18-503, 18-504, 18-505, 1 8-506, 1 8-507, 18-508, 1 8-509, 18-510, 18-51 1 , or 18-512 of an ALP (e.g., SEQ ID NOs: 2-6), and may include additional C-terminal and/or N-terminal portions. Biological activity of such fragments is tested in standard assays known in the art, e.g., by a non-compartmental analysis (NCA) to calculate NCA (NCA) to calculate NCA.
  • NCA non-compartmental analysis
  • HPP hyperphosphatasia
  • ALPL alkaline phosphatase, liver/bone/kidney
  • TAALP tissue-nonspecific alkaline phosphatase
  • HPP may be further characterized as infantile HPP, childhood HPP, perinatal HPP (e.g., benign perinatal HPP or lethal perinatal HPP), odonto-HPP, adolescent HPP, or adult HPP.
  • adolescent HPP describes a patient having HPP that is about 12 years of age to about 18 years of age
  • adult HPP describes a patient having HPP that is older than about 18 years of age.
  • HPP phenotype refers to any one of rickets (defect in growth plate cartilage), osteomalacia, elevated blood and/or urine levels of inorganic pyrophosphate (PPi), phosphoethanolamine (PEA), or pyridoxal 5'-phosphate (PLP), seizure, bone pains, and calcium pyrophosphate dihydrate crystal deposition (CPPD) in joints leading to chondrocalcinosis,
  • a HPP phenotype can be documented by one or more of growth retardation with a decrease of long bone length (including but not limited to femur, tibia, humerus, radius, and/or ulna), a decrease of the mean density of total bone and a decrease of bone mineralization in bones such as femur, tibia, ribs and metatarsi, and phalange, a decrease in teeth mineralization, and a premature loss of deciduous teeth (e.g., aplasia, hypoplasia, or dysplasia of dental cementum).
  • correction or prevention of bone mineralization defect may be observed by one or more of the following: an increase of long bone length, an increase of
  • na ' ive patient a patient having HPP (e.g., an adolescent or adult) that has never received treatment with a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • HPP e.g., an adolescent or adult
  • TNALP sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • peptide refers to any chain of two or more natural or unnatural amino acid residues, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally-occurring or non-naturally occurring polypeptide or peptide, as is described herein.
  • post-translational modification e.g., glycosylation or phosphorylation
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” is meant at least one carrier or excipient, respectively, which is physiologically acceptable to the treated patient while retaining the therapeutic properties of the compound with which it is administered.
  • One exemplary pharmaceutically acceptable carrier substance is physiological saline.
  • the pharmaceutically acceptable carrier can include sodium chloride (e.g., 1 50 mM sodium chloride) and sodium phosphate (e.g., 25 mM sodium phosphate).
  • sodium chloride e.g., 1 50 mM sodium chloride
  • sodium phosphate e.g., 25 mM sodium phosphate
  • Other physiologically acceptable carriers and their formulations are known to those skilled in the art and described, e.g., in Remington's Pharmaceutical Sciences (20th edition), A. Gennaro, Ed., 2000, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • composition a composition containing a polypeptide or nucleic acid molecule as described herein formulated with at least one pharmaceutically acceptable excipient, diluent, or carrier.
  • the pharmaceutical composition may be manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment or prevention of a disease or event in a patient.
  • Pharmaceutical compositions can be formulated, for example, for subcutaneous administration, intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use), for oral administration (e.g., a tablet, capsule, caplet, gelcap, or syrup), or any other formulation described herein, e.g., in unit dosage form.
  • physical impairments refers to a physiological condition, such as bone weakness and muscle weakness, associated with HPP that can restrict or eliminate, e.g., walking ability, functional endurance, and ability to perform activities of daily living (ADL) of a patient.
  • physical impairments may restrict or eliminate a patient's ability to perform ADL, which are routine activities that healthy subjects perform on a daily basis without requiring assistance, such as functional mobility or transferring (e.g., walking), bathing and showering, dressing, self-feeding, and personal hygiene and grooming.
  • compositions including a sALP fusion polypeptide, such as asfotase alfa can be administered to a patient (e.g., an adolescent or adult having HPP) to decrease the severity and/or frequency of physical impairments associated with an HPP phenotype and/or to increase the walking ability of the patient (e.g., the walking ability determined from the distance walked by the patient over six minutes).
  • physiologically active refers to a sALP that hydrolyzes
  • PEA phosphoethanolamine
  • PPi inorganic pyrophosphate
  • PLP pyridoxal 5'-phosphate
  • sALP soluble alkaline phosphatase
  • extracellular domain of an alkaline phosphatase are used interchangeably and refer to a soluble, non-membrane bound alkaline phosphatase (ALP) or a domain or a biologically active fragment of the soluble, non-membrane bound ALP.
  • sALPs include, for example, an alkaline phosphatase lacking a C-terminal glycolipid anchor (GPI signal sequence, e.g., polypeptides including or consisting of the amino acid residues 1 8-502 of a human TNALP (SEQ ID NOs: 2, 3, 4, 5, or 6)).
  • a TNALP may include, e.g., a polypeptide including or consisting of amino acid residues 1 -485 of SEQ I D NO: 1 , such as asfotase alfa, or a polypeptide variant having at least 95% sequence identity to the amino acid residues 1 -485 of SEQ ID NO: 1 .
  • sALPs further include, for example, mammalian orthologs of human TNALP, such as a rhesus TNALP (SEQ ID NO: 7), a rat TNALP (SEQ ID NO: 8), a canine TNALP (SEQ ID NO: 9), a porcine TNALP (SEQ ID NO: 10), a murine TNALP (SEQ ID NO: 1 1 ), a bovine TNALP (SEQ ID NOs: 12-14), or a feline TNALP (SEQ ID NO: 1 5).
  • mammalian orthologs of human TNALP such as a rhesus TNALP (SEQ ID NO: 7), a rat TNALP (SEQ ID NO: 8), a canine TNALP (SEQ ID NO: 9), a porcine TNALP (SEQ ID NO: 10), a murine TNALP (SEQ ID NO: 1 1 ), a bovine TNALP (SEQ ID NOs: 12-14), or
  • sALPs also include soluble, non-membrane-bound forms of human PALP (e.g., polypeptides including or consisting of amino acid residues 1 8-502 of SEQ ID NOs: 16 or 17), GCALP (e.g., polypeptides including or consisting of amino acid residues 18-502 of SEQ ID NO: 18), and IALP (e.g., polypeptides including or consisting of amino acid residues 18-502 of SEQ ID NO: 19), and additional variants and analogs thereof that retain alkaline phosphatase activity, e.g., the ability to hydrolyze PPi.
  • human PALP e.g., polypeptides including or consisting of amino acid residues 1 8-502 of SEQ ID NOs: 16 or 17
  • GCALP e.g., polypeptides including or consisting of amino acid residues 18-502 of SEQ ID NO: 18
  • IALP e.g., polypeptides including or consisting of amino acid
  • a sALP in particular, lacks the N-terminal signal peptide (e.g., aa 1 -1 7 of SEQ ID NOs: 2-6, 8, 1 1 -13, or 15 or aa 1 -25 of SEQ ID NO: 7).
  • the N-terminal signal peptide e.g., aa 1 -1 7 of SEQ ID NOs: 2-6, 8, 1 1 -13, or 15 or aa 1 -25 of SEQ ID NO: 7).
  • sALP fusion polypeptide is meant a polypeptide having the structure Z-sALP-Y-spacer-X-W n - V, Z-Wn-X-spacer-Y-sALP-V, Z-sALP-Y-Wn-X-spacer-V, and Z-Wn-X-sALP-Y-spacer-V.
  • the sALP fusion polypeptide can be Z-sALP-Y-spacer-X-Wn-V or Z-Wn-X-spacer-Y-sALP-V, such as hTNALP- Fc-Dio (e.g., asfotase alfa; the amino acid sequence SEQ ID NO: 1 ).
  • X, Y, Z, V, the spacer, and/or W n can be absent or an amino acid sequence of at least one amino acid.
  • X, Y, Z, and V may be a dipeptide sequence (e.g., leucine-lysine or aspartic acid-isoleucine), such as a two residue linker at the Y position (e.g., leucine-lysine) and a two residue linker at the X position (e.g., aspartic acid-isoleucine).
  • Spacers include, for example, a Fc region of an immunoglobulin, such as the amino acid sequence of SEQ ID NO: 20.
  • D aspartate
  • E glutamate residues
  • signal peptide is meant a short peptide (5-30 amino acids long) at the N-terminus of a polypeptide that directs a polypeptide towards the secretory pathway (e.g., the extracellular space).
  • the signal peptide is typically cleaved during secretion of the polypeptide.
  • the signal sequence may direct the polypeptide to an intracellular compartment or organelle, e.g., the Golgi apparatus.
  • a signal sequence may be identified by homology, or biological activity, to a peptide with the known function of targeting a polypeptide to a particular region of the cell.
  • a signal peptide can be one that is, for example, substantially identical to amino acid residues 1 -17 of SEQ ID NOs: 2-6 or amino acid residues 1 -25 of SEQ ID NO: 7.
  • a polypeptide or nucleic acid sequence is referred to as having "at least X% sequence identity" to a reference sequence, wherein "X" is a real number, it is meant that at least X percent of the amino acid residues or nucleotides in the polypeptide or nucleic acid are identical to those of the reference sequence when the sequences are optimally aligned.
  • An optimal alignment of sequences can be determined in various ways that are within the skill in the art, for instance, the Smith Waterman alignment algorithm (Smith et al., J. Mol. Biol. 147:195-7, 1981 ) and BLAST (Basic Local Alignment Search Tool; Altschul et al., J. Mol. Biol. 21 5: 403-10, 1990).
  • patient refers to a mammal, including, but not limited to, a human or a non-human mammal, such as a bovine, equine, canine, ovine, or feline.
  • Parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, subcutaneous, intradermal, intravenous, intranasal, intraocular, pulmonary, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.
  • terapéuticaally effective amount is meant an amount of a polypeptide or nucleic acid molecule described herein that is sufficient to substantially improve, treat, prevent, delay, suppress, or arrest at least one symptom of HPP.
  • a therapeutically effective amount of a composition described herein may depend on the severity of the disorder being treated and the condition, weight, and general state of the patient and can be determined by an ordinarily-skilled artisan with consideration of such factors.
  • a therapeutically effective amount of a composition described herein can be administered to a patient in a single dose or in multiple doses administered over a period of time.
  • treating is meant the medical management of a patient with the intent to cure, ameliorate, stabilize, reduce the likelihood of, or prevent HPP and/or management of a patient exhibiting or likely to have HPP, e.g., by administering a pharmaceutical composition.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement or associated with the cure of a disease, pathological condition, disorder, or event, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, disorder, or event.
  • this term includes palliative treatment, that is, treatment designed for the relief or improvement of at least one symptom rather than the curing of the disease, pathological condition, disorder, or event; symptomatic treatment, that is, treatment directed toward constitutional symptoms of the associated disease, pathological condition, disorder, or event; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, disorder, or event, e.g., in a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease, pathological condition, disorder, or event; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, disorder, or event.
  • walking ability refers to the ability of a patient (e.g., an adolescent or adult having HPP) to lift and set down each foot in turn. Walking ability may be assessed by tests, in particular, the Six Minute Walk Test (6MWT). See the American Thoracic Society statement: guidelines for the six- minute walk test (American Journal of Respiratory and Critical Care Medicine, 166(1 ):1 1 1 -7, 2002), hereby incorporated by reference in its entirety. The 6MWT is determined from the distance (e.g., in meters) that a patient walks on a flat, hard surface in a period of six minutes.
  • 6MWT Six Minute Walk Test
  • the 6MWT value is then compared to the predicted 6MWT value of an untreated subject (e.g., an untreated subject of about the same age, height, and/or gender) or a healthy subject (e.g., a healthy subject of about the same age, height, and/or gender), which may be expressed as a percentage of the predicted 6MWT value.
  • an untreated subject e.g., an untreated subject of about the same age, height, and/or gender
  • a healthy subject e.g., a healthy subject of about the same age, height, and/or gender
  • Figure 1 is an image showing the study design for administering asfotase alfa to adolescents and adults having hypophosphatasia (HPP) over a time period of four years, including an initial phase of treatment with asfotase alfa (from baseline) to six months and an extension phase of treatment with asfotase alfa (from six months of treatment to four or more years of treatment).
  • An X represents that a patient discontinued treatment with asfotase alfa.
  • Figures 2A-2D are graphs showing the PPi and PLP concentrations for individual adolescent and adult patients (Fig. 2A), the median change in PPi and PLP concentrations after six months of treatment with asfotase alfa (Fig. 2B), and the median inorganic pyrophosphate (PPi; Fig. 2C) and median pyridoxal 5'-phosphate (PLP; Fig. 2D) concentrations in plasma samples from adolescent and adult HPP patients during treatment with asfotase alfa over a time period of four years.
  • the upper normal limit and lower normal limit of both PPi and PLP concentrations for healthy subjects of about 12 to 18 years of age and patients over about 1 8 years of age are shown.
  • the number (n) of patients assessed for plasma PPi and PLP concentrations is shown above each time point.
  • a * indicates that the dosage groups (2.1 mg/kg/week and 3.5 mg/kg/week) were combined.
  • the initial 6 control patients do not have data at year 4 due to the 6 month offset.
  • the time period during which treatment with asfotase alfa was increased to a dosage of 6 mg/kg/week via protocol amendment is shown.
  • Figures 3A-3B are graphs showing the median change from baseline in the 6MWT value of adolescent and adult HPP patients at six months of treatment with asfotase alfa (Fig. 3A) and the median Six Minute Walk Test (6MWT) value of adolescent and adult HPP patients during treatment with asfotase alfa over a time period of four years (Fig. 3B).
  • the median 6MWT value is shown as the percentage of the predicted 6MWT relative to the normal range for healthy subjects of about the same age and height.
  • the normal range for healthy subjects of the same age and height is 80 to 100% of the predicted median distance walked (shown in green).
  • a * indicates that the dosage groups (2.1 mg/kg/week and 3.5 mg/kg/week) were combined.
  • the initial 6 control patients do not have data at year 4 due to the 6 month offset.
  • the time period during which treatment with asfotase alfa was increased to a dosage of 6 mg/kg/week via protocol amendment is shown (Fig. 3B).
  • Figures 4A-4C are images and a graph of the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) strength tests (Fig. 4A), BOT-2 running speed and agility tests (Fig. 4B), and the average BOT-2 strength scores and BOT-2 running speed and agility scores of adolescent and adult HPP patients after administration of asfotase alfa over a time period of four years (Fig. 4C).
  • the median of the BOT-2 scores for each time interval baseline, 6 months, 1 year, 2 years, 3 years, 4 years
  • a * indicates that the dosage groups (2.1 mg/kg/week and 3.5 mg/kg/week) were combined.
  • the initial 6 control patients did not have data for the year 4 time point due to the 6 month offset.
  • asfotase alfa SEQ ID NO: 1 , STRENSIQ®, Alexion Pharmaceuticals, Inc.
  • HPP hypophosphatasia
  • adolescents having HPP e.g., adolescents having HPP of about 12 to about 18 years of age
  • adults having HPP e.g., adults having HPP older than about 18 years of age
  • an extended period of time e.g., at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient.
  • asfotase alfa (SEQ ID NO: 1 ) can be administered to treat adolescents and adults with HPP exhibiting physical impairments (e.g., bone or muscle weakness) and decreased walking ability relative to an untreated subject having HPP (e.g., an untreated subject having HPP of about the same age, same gender, and/or height).
  • the adolescent having HPP or adult having HPP can be a na ' ive patient that has not previously received treatment with asfotase alfa (SEQ ID NO: 1 ).
  • asfotase alfa SEQ ID NO: 1
  • asfotase alfa can be administered to an adolescent having HPP or an adult having HPP with decreased walking ability, such that the Six Minute Walk Test (6MWT) value of the adolescent or adult is less than about 80% of the predicted 6MWT value, such as the predicted 6MWT value for an untreated subject having HPP (e.g., an untreated subject having HPP of about the same age, same gender, and/or height).
  • 6MWT Six Minute Walk Test
  • the adult or adolescent having HPP exhibits decreased reliance on an assistive device for mobility generally or for walking specifically, such as a wheelchair, a wheeled walker, a cane, or an orthotic, after administration of the sALP.
  • BOT-2 Bruininks-Oseretsky Test of Motor Proficiency 2 nd Edition
  • asfotase alfa can be administered to an adolescent having HPP or an adult having HPP having an average BOT-2 running speed and agility score of less than about 7.
  • asfotase alfa can be administered to an adolescent having HPP or an adult having HPP having an average BOT-2 strength score of less than about 14.
  • adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age
  • PPi inorganic pyrophosphate
  • a plasma sample from the adolescent or adult may have a PPi concentration of about 5 ⁇ to about 6 ⁇ .
  • a plasma sample from the patient may have a PLP concentration of about 50 ng/ml to about 300 ng/ml.
  • asfotase alfa may be administered to an adolescent having HPP or an adult having HPP for an extended period of time, e.g., at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • sALPs such as a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1
  • an adolescent having HPP or an adult having HPP for an extended period of time, e.g., at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age
  • Adolescents having HPP can be treated by administering a sALP (such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) across a range of ages, e.g., about 12 to about 13 years of age, about 13 to about 15 years of age, about 14 to about 1 6 years of age, about 12 to about 16 years of age, about 15 to about 1 6 years of age, about 14 to about 1 7 years of age, about 15 to about 17 years of age, about 16 to about 1 8 years of age, or about 14 to about 18 years of age.
  • a sALP such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or
  • a sALP such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a range of ages e.g., about 18 to about 20 years of age, about 20 to about 25 years of age, about 25 to about 30 years of age, about 30 to about 35 years of age, about 35 to about 40 years of age, about 40 to about 45 years of age, about 45 to about 50 years of age
  • Adolescents e.g., adolescents having HPP of about 12 to about 1 8 years of age
  • adults e.g., adults having HPP older than about 18 years of age
  • a sALP such as TNALP
  • a sALP fusion polypeptide such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • an adolescent having HPP or an adult having HPP can exhibit, e.g., physical impairments and impaired walking ability relative to an adolescent without HPP or an adult without HPP, respectively.
  • the adolescent having HPP or adult having HPP can be a naive patient that has not previously received treatment with a sALP (such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • a sALP such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g
  • the method involves administering a sALP (such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) to an adolescent having HPP or an adult having HPP, such as administering a sALP for a period of least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP such as TNALP, for example, a sALP fusion polypeptide, such as the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant
  • a sALP such as asfotase alfa
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age
  • a 6MWT value of less than about 80% of the predicted 6MWT value of the patient (e.g., relative to an untreated subject of about the same age, the same gender, and/or the same height)
  • a plasma PPi concentration of about 5 ⁇ or greater
  • a plasma PLP concentration of about 50 ng/ml or greater an average BOT-2 running speed and agility score of less than about 7, and/or an average BOT-2 strength score of less than about 14.
  • the 6MWT value of the patient can be compared to the 6MWT value at baseline of the patient.
  • the 6MWT value of the adolescent or adult having HPP can be compared to the 6MWT value of a healthy patient.
  • the sALP e.g., asfotase alfa
  • the sALP can be administered for a period of least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the methods can include determining the 6MWT, BOT-2 running speed and agility score, BOT-2 strength score, plasma PPi concentration, and/or plasma PLP concentration prior to administering a sALP, such as asfotase alfa, as described herein.
  • a sALP such as asfotase alfa
  • each of the described metrics e.g., the 6MWT value, the BOT-2 strength score, BOT-2 running speed and agility score, plasma PPi concentrations, and plasma PLP concentrations
  • a patient having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • improvements relative to a certain value or score demonstrate that the sALP is effective for treating HPP.
  • a sALP when administration of a sALP to an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age) results in an average increase in the BOT-2 running speed and agility score to about 9 or greater, in which the adolescent or adult previously had an average BOT-2 strength score of less than about 7, then the sALP treatment is effective at treating, e.g., physical impairments associated with HPP.
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age
  • the dosage and/or frequency of sALP administration can be changed in order to determine the effective amount of the sALP for the adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 1 8 years of age).
  • the adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 1 8 years of age
  • the dosage of the sALP such as TNALP for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the dosage of the sALP such as TNALP can be increased from, e.g., about 2.1 mg/kg/week or about 3.5 mg/kg/week to about 6 mg/kg/week or about 9 mg/kg/week.
  • Asfotase alfa is administered, as described herein, to treat adolescent HPP or adult HPP.
  • patients having adolescent HPP e.g., adolescents having HPP of about 12 to about 18 years of age
  • adult HPP e.g., adults having HPP older than about 18 years of age
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • at least one year e.g., at least two years, at
  • an HPP phenotype of, e.g., adolescent HPP or adult HPP, is treated with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa.
  • the methods are useful for alleviating any of the symptoms of HPP described herein, particularly when the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) is administered for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the methods are useful for treating symptoms of adolescent and adult HPP, including, but not limited to, premature loss of teeth due to aplasia, hypoplasia, or dysplasia of dental cementum that connects the tooth root with the periodontal ligament; rickets (osteomalacia); skeletal deformities, such as bowed legs and enlarged wrists, knees, and ankles as a result of flared metaphyses; short stature; muscle weakness, skeletal pain; stiffness; bone fractures; pseudofractures; arthritis;
  • pyrophosphate arthropathy calcium pyrophosphate dihydrate crystal deposition; altered physical function including walking ability; elevated blood and/or urine levels of inorganic pyrophosphate (PPi), phosphoethanolamine (PEA), and/or urine levels of pyridoxal 5'-phosphate (PLP); hypomineralization; rachitic ribs; hypercalciuria; HPP-related seizure; inadequate weight gain; and/or calcium pyrophosphate dihydrate crystal deposition.
  • PPi inorganic pyrophosphate
  • PEA phosphoethanolamine
  • PGP pyridoxal 5'-phosphate
  • hypomineralization rachitic ribs
  • hypercalciuria HPP-related seizure
  • inadequate weight gain and/or calcium pyrophosphate dihydrate crystal deposition.
  • any of the above mentioned symptoms can be treated with a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • Exemplary metrics useful for evaluating the need for or the efficacy of treatment using a sALP include (1 ) the Bruininks-Oseretsky Test of Motor Proficiency 2 nd Edition (BOT-2), (2) the Six Minute Walk Test (6MWT), and (3) plasma PPi and PLP concentrations, which are described in further detail below.
  • Adolescents having HPP e.g., adolescents having HPP of about 12 to about 18 years of age or adults having HPP (e.g., adults having HPP older than about 18 years of age) can be identified for treatment with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) using the BOT-2).
  • the BOT-2 can be used to evaluate physical impairments and mobility restrictions in an adolescents having HPP or an adult having HPP to generate a BOT-2 score for the adolescent or adult.
  • the BOT-2 includes a range of tests to evaluate physical impairments of a patient having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age), which can be performed with, e.g., a kit including the tests.
  • HPP e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • the BOT-2 provides composite BOT-2 scores in the following areas: strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination.
  • the adolescent or adult having HPP can perform sit-ups, v-ups, standing long jump, wall sit, and/or push-ups to determine the BOT-2 strength score; the adolescent or adult having HPP can step over a balance beam and/or perform a shuttle run, two-legged side hop, and/or one-legged side hop to determine the BOT-2 running speed and agility score; the adolescent or adult having HPP can cut out a circle and/or connect dots to determine the BOT-2 fine motor precision score; the adolescent or adult having HPP can copy a star and/or copy a square to determine the BOT-2 fine motor integration score; the adolescent or adult having HPP can transfer pennies, sort cards, and/or string blocks to determine the manual dexterity score; the adolescent or adult having HPP can tap his or her foot and finger and/or perform jumping jacks to determine the BOT-2 bilateral coordination score; the adolol
  • An adolescent having HPP e.g., adolescents having HPP of about 12 to about 1 8 years of age
  • an adult having HPP e.g., adults having HPP older than about 18 years of age
  • could perform tests in one or more of described areas to generate a BOT-2 score indicative of physical impairments in the adolescent or adult.
  • an adolescent or adult having HPP could perform one or more tests to determine the BOT-2 score of the adolescent or adult, e.g., the adolescent or adult could perform one or more of sit-ups, v-ups, standing long jump, wall sit, and push-ups to determine the BOT-2 strength score.
  • BOT-2 score e.g., a BOT-2 strength score
  • Each of the BOT-2 scores (strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination) of the patient having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age) can be compared to the BOT-2 score of patients without HPP (e.g., an adolescent without HPP of about 12 to about 18 years of age or an adult without HPP older than about 18 years of age) to, e.g., determine the standard deviation of the BOT-2 score.
  • HPP e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age
  • Each of the BOT-2 scores (e.g., strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination) of the patient having HPP can be compared to the BOT-2 score of other HPP patients to, e.g., determine the average BOT-2 score for the HPP patient.
  • BOT-2 scores range from about 0 to equal to or less than about 25, in which a score of greater than about 1 0 is considered representative of healthy subjects (e.g., patients without HPP).
  • Patients with an average BOT-2 score (e.g., strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination scores) of less than about 10 can be treated with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), such as by administering a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or
  • an HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a BOT-2 running speed and agility score of less than 10 e.g, about 0, about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a period of at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • an HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a BOT-2 strength score of less than 14 e.g, about 0, about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, or about 14
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a period of at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the
  • the methods result in an improvement in the BOT-2 score (e.g., strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and/or upper-limb coordination score) of a HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age).
  • a HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age.
  • treatment with a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • treatment with a sALP for a period of at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • treatment with a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • treatment with a sALP for a period of at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient
  • a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient)
  • a sALP
  • the increase in the BOT-2 score can be sustained throughout administration of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), e.g., for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the decrease in physical impairments can be sustained throughout administration of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), e.g., for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a period of at least one year
  • the BOT-2 scores (strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upper-limb coordination scores) of a HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age) can be used singly or in combination to assess treatment efficacy using a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), in which improvements relative to a certain test score demonstrate that the sALP is effective for treating physical impairments associated with HPP.
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity
  • a sALP when administration of a sALP to a HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age) results in an average increase in the BOT-2 running speed and agility score to about 9 or greater, in which the patient previously had an average BOT-2 running speed and agility score of less than about 7, then the sALP is considered to be effective at, e.g., treating physical impairments associated with HPP.
  • a HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • an increase of at least two points or more e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 points
  • an increase of at least two points or more indicates efficacy (e.g., when coupled with a sustained high score for greater than 1 year of treatment).
  • a HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age
  • the adolescent or adult having HPP could perform one or more of sit-ups, v- ups, standing long jump, wall sit, and push-ups to determine the BOT-2 strength score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP could perform one or more of balance beam, a shuttle run, two-legged side hop, and/or one-legged side hop to determine the BOT-2 running speed and agility score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP can cut out a circle and/or connect dots to determine the BOT-2 fine motor precision score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP can copy a star and/or copy a square to determine the BOT-2 fine motor integration score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP could perform one or more of transferring pennies, sorting cards, and stringing blocks to determine the BOT-2 manual dexterity score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP can tap his or her foot and finger and/or perform jumping jacks to determine the BOT-2 bilateral coordination score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP can walk forward on a line and/or stand on one leg on a balance beam to determine the BOT-2 balance score and assess the treatment efficacy of sALP administration.
  • the adolescent or adult having HPP can throw a ball at a target and/or catch a tossed ball to determine the BOT-2 upper-limb coordination score and assess the treatment efficacy of sALP administration.
  • the dosage and/or frequency of sALP administration can be changed in order to determine the effective amount of the sALP for the HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age).
  • the dosage of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be increased from, e.g., about 2.1 mg/kg/week or about 3.5 mg/kg/week to about 6 mg/kg/week or about 9 mg/kg/week.
  • TNALP for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • Adolescents having HPP e.g., adolescents having HPP of about 12 to about 18 years of age
  • adults having HPP e.g., adults having HPP older than about 18 years of age
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • 6MWT 6MWT
  • the 6MWT can be used to evaluate walking ability in an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age) to generate a 6MWT value for the adolescent or adult.
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age
  • the 6MWT can be performed indoors or outdoors using a flat, straight, enclosed corridor (e.g., of about 30 meters in length) with a hard surface.
  • a stopwatch or other timer can be used to track the time and a mechanical counter or other device can be used to determine the distance (e.g., in meters) that the HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age) walks.
  • the length of the corridor can be marked every three meters to determine the number of meters walked by the HPP patient, with the turnaround point at 30 meters and the starting line also marked.
  • the distance walked by the patient in six minutes can then be compared to the predicted number of meters walked, e.g., by an untreated subject of about the same age, the same gender, and/or the same height, and expressed as a percentage value to generate the 6MWT value of the patient.
  • the 6MWT value of the patient e.g., the adolescent or adult having HPP
  • the 6MWT value of the adolescent or adult having HPP can be compared to the 6MWT value of a healthy patient.
  • HPP patients e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years,
  • an HPP patient with an average 6MWT of less than about 80% of the predicted 6MWT value can be treated with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the methods can result in an improvement in the 6MWT value of a HPP patient (e.g., an adolescent having HPP of about 1 1 8 years of age or an adult having HPP older than about 18 years of age).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • treatment with a sALP for a period of at least one year e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient
  • result in an average increase in the 6MWT value to about 80% or greater of the predicted 6MWT value of the patient result in an average increase in the
  • the increase in the 6MWT value of the HPP patient can be sustained throughout administration of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), e.g., for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the 6MWT value increases to greater than about 80% of the predicted 6 MWT value of the patient and remains at ⁇ 10% of the increased 6MWT value during treatment with the sALP (e.g., asfotase alfa).
  • sALP e.g., asfotase alfa
  • the improvement in walking ability of the HPP patient can be sustained throughout administration of the sALP, e.g., for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the HPP patient exhibits decreased reliance on an assistive device for walking, such as a wheelchair, a wheeled walker, a cane, or an orthotic during treatment with the sALP.
  • the dosage and/or frequency of sALP administration can be changed in order to determine the effective amount of the sALP for the HPP patient (e.g., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age).
  • the dosage of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be increased from, e.g., about 2.1 mg/kg/week or about 3.5 mg/kg/week to about 6 mg/kg/week or about 9 mg/kg/week.
  • Patients having HPP can be identified for treatment with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) by determining the PPi and/or PLP concentrations in a plasma sample from the patient.
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • PPi and PLP concentrations in a plasma sample can be used to evaluate ALP activity for the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age).
  • HPP patients In comparison to healthy subjects (e.g., healthy subjects of about the same age, same gender, and/or same height), HPP patients typically exhibit elevated plasma concentrations of PPi and PLP, such as a PPi concentration of about 5 ⁇ or greater and/or a PLP concentration of about 50 ng/ml or greater.
  • the lower normal limit for plasma PPi concentrations of healthy adults is about 1 ⁇ , while the upper normal limit is about 5.9 ⁇ .
  • the lower normal limit for plasma PPi concentrations of adolescent adults is about 0.8 ⁇ , while the upper normal limit is about 4.9 ⁇ .
  • the lower normal limit for plasma PLP concentrations of healthy adults is less than about 10 ng/ml, while the upper normal limit is about 60 ng/ml.
  • the lower normal limit for plasma PLP concentrations of adolescent adults is less than about 1 0 ng/ml, while the upper normal limit is less than about 25 ng/ml.
  • HPP patients e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a sALP for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years,
  • an HPP patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age
  • a PPi concentration of about 5 ⁇ or greater can be treated with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having
  • an HPP patient with a PLP concentration of about 50 ng/ml or greater can be treated with a sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • the methods result in an average decrease in PPi and/or PLP concentrations in a plasma sample from the patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age).
  • a plasma sample from the patient e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age.
  • treatment with a sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • treatment with a sALP for a period of at least one year results in an average decrease in PPi concentrations in a plasma sample from the patient of about 25% or greater (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, or more than 60%) relative to PPi concentrations in a plasma sample from the patient prior to administration of the sALP.
  • treatment with a sALP results in an average decrease in PLP
  • concentrations in a plasma sample from the patient of about 50% or greater (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%) relative to PLP concentrations in a plasma sample from the patient prior to administration of the sALP.
  • the decrease in the plasma PPi and/or PLP concentrations of the HPP patient can be sustained throughout administration of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), e.g., for a period of at least one year (e.g., at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or longer than ten years, such as for the lifetime of the patient).
  • the sALP such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase
  • the plasma PPi concentration decreases by about 25% and remains at ⁇ 10% of the decreased plasma PPi concentration during treatment with the sALP and/or the plasma PLP concentration decreases by about 50% and remains at ⁇ 10% of the decreased plasma PLP concentration during treatment with the sALP
  • the dosage and/or frequency of sALP administration can be changed in order to determine the effective amount of the sALP for the HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 18 years of age).
  • the dosage and/or frequency of sALP administration can be changed in order to determine the effective amount of the sALP for the HPP patient (e.g., an adolescent having HPP of about 12 to about 18 years of age or an adult having HPP older than about 1 8 years of age).
  • the dosage of the sALP (such as TNALP, for example the sALP fusion polypeptide of SEQ I D NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ I D NO: 1 , e.g., asfotase alfa) can be increased from , e.g. , about 2.1 mg/kg/week or about 3.5 mg/kg/week to about 6 mg/kg/week or about 9 mg/kg/week.
  • TNALP for example the sALP fusion polypeptide of SEQ I D NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ I D NO: 1 , e.g., asfotase alfa
  • Asfotase alfa is a human TNALP (hTNALP; SEQ I D NO: 1 ) fusion polypeptide formulated for the treatment of HPP.
  • asfotase alfa SEQ ID NO: 1
  • Alkaline phosphatases encompass a group of enzymes that catalyze the cleavage of a phosphate moiety (e.g. , hydrolysis of pyrophosphate, PPi).
  • ALP alkaline phosphatase
  • TAALP tissue nonspecific alkaline phosphatase
  • PKALP placental alkaline phosphatase
  • any polypeptide having the identical or similar catalytic site structure and/or enzymatic activity of ALP can be used (e.g.
  • sALP as a sALP or a sALP fusion polypeptide as defined herein
  • HPP patients such as adolescents or adults having H PP (e.g ., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age).
  • H PP e.g ., an adolescent having HPP of about 12 to about 1 8 years of age or an adult having HPP older than about 1 8 years of age.
  • Bone delivery conjugates including sALP are further described in PCT publication Nos: WO 2005/1 03263 and WO 2008/1 38131 .
  • TNALPs that can be used according to the methods described herein include, e.g., human TNALP (Accession Nos. NP_000469, AAI1 091 0, AAH90861 , AAH661 1 6, AAH21289, and AAI261 66) ; rhesus TNALP (Accession No. XP_01 1 0971 7) ; rat TNALP (Accession No. NP_0371 91 ) ; dog TNALP (Accession No. AAF6451 6) ; pig TNALP (Accession No. AAN64273), mouse (Accession No. NP_031457), cow TNALP (Accession Nos.
  • human TNALP Accession Nos. NP_000469, AAI1 091 0, AAH90861 , AAH661 1 6, AAH21289, and AAI261 66
  • rhesus TNALP Accession No. XP_01 1
  • TNALP can be a recombinant human TNALP (e.g., SEQ ID NO: 1 , asfotase alfa; see U.S. Patent Nos. 7,763,712 and 7,960,529, incorporated herein by reference in their entirety) used for the treatment of HPP patients, such as adolescents with HPP (e.g. , adolescents having HPP of about 12 to about 1 8 years of age) or adults with HPP (e.g. , adults having H PP older than about 1 8 years of age).
  • the TNALP can also be one that exhibits at least about 95% sequence identity to the polypeptide or nucleic acid sequence of the above-noted TNALPs. Soluble Alkaline Phosphatases
  • the ALPs that can be used in the methods described herein include soluble (e.g., extracellular or non-membrane-bound) forms of any of the alkaline phosphatases described herein.
  • the sALP can be, for example, a soluble form of human tissue non-specific alkaline phosphatase (human TNALP
  • hTNALP phosphoethanolamine
  • PPi inorganic pyrophosphate
  • PDP pyridoxal 5'-phosphate
  • a sALP is one that is catalytically competent to improve skeletal mineralization in bone.
  • the methods further include nucleic acids encoding the sALPs described herein that can be used to treat the conditions described herein, e.g., HPP, such as adolescents with HPP (e.g., adolescents having HPP of about 12 to about 18 years of age) or adults with HPP (e.g., adults having HPP older than about 18 years of age).
  • HPP such as adolescents with HPP (e.g., adolescents having HPP of about 12 to about 18 years of age) or adults with HPP (e.g., adults having HPP older than about 18 years of age).
  • TNALP is a membrane-bound protein anchored by a glycolipid moiety at the C-terminal (Swiss- Prot, P05186).
  • This glycolipid anchor (GPI) is added post-translationally after the removal of a hydrophobic C-terminal end, which serves both as a temporary membrane anchor and as a signal for the addition of the GPI. While the GPI anchor is located in the cell membrane, the remaining portions of TNALP are extracellular.
  • TNALP e.g., human TNALP (hTNALP)
  • hTNALP human TNALP
  • TNALP can be engineered to replace the first amino acid of the hydrophobic C-terminal sequence (an alanine) with a stop codon, thereby producing an engineered hTNALP that contains all amino acid residues of the native anchored form of TNALP and lacks the GPI membrane anchor.
  • the position of the GPI membrane anchor will vary in different ALPs and can include, e.g., the last 10, 12, 14, 16, 18, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 45, 50, or more amino acid residues on the C-terminus of the polypeptide.
  • Recombinant sTNALP can include, e.g., amino acids 1 to 502 (18 to 502 when secreted), amino acids 1 to 501 (18 to 501 when secreted), amino acids 1 to 504 (18 to 504 when secreted), amino acids 1 to 505 (1 8-505 when secreted), or amino acids 1 to 502.
  • amino acids 1 to 502 18 to 502 when secreted
  • amino acids 1 to 501 18 to 501 when secreted
  • amino acids 1 to 504 18 to 504 when secreted
  • amino acids 1 to 505 (1 8-505 when secreted
  • TNALP In addition to the C-terminal GPI anchor, TNALP also has an N-terminal signal peptide sequence.
  • the N-terminal signal peptide is present on the synthesized protein when it is synthesized, but cleaved from TNALP after translocation into the ER.
  • the sALPs include both secreted (i.e., lacking the N-terminal signal) and non-secreted (i.e., having the N-terminal signal) forms thereof.
  • the position of the N-terminal signal peptide will vary in different alkaline phosphatases and can include, for example, the first 5, 8, 10, 1 1 , 12, 13, 14, 1 5, 16, 1 7, 18, 1 9, 20, 21 , 22, 23, 24, 25, 27, 30, or more amino acid residues on the N-terminus of the polypeptide.
  • One of skill in the art can predict the position of a signal sequence cleavage site, e.g., by an appropriate computer algorithm such as that described in Bendtsen et al. (J. Mol. Biol. 340(4) :783-795, 2004) and available on the Web at www.cbs.dtu.dk/services/SignalP/.
  • the methods can also be performed using sALP consensus sequences derived from the extracellular domain of ALP isozymes (e.g., TNALP, PALP, GCALP, IALP, etc.).
  • ALP isozymes
  • the present disclosure also provides other soluble human ALP isozymes, i.e., without the peptide signal, preferably comprising the extracellular domain of the ALPs.
  • the sALPs also include polypeptide sequences satisfying a consensus sequence derived from the ALP extracellular domain of human ALP isozymes and of mammalian TNALP orthologs (human, mouse, rat, cow, cat, and dog) or a consensus derived from the ALP extracellular domain of just mammalian TNALP orthologs (human, mouse, rat, cow, cat, and dog).
  • the sALPs also include those which satisfy similar consensus sequences derived from various combinations of these TNALP orthologs or human ALP isozymes. Such consensus sequences are given, for example, in WO 2008/138131 .
  • sALPs of the present methods can include not only the wild-type sequence of the sALPs described above, but any polypeptide having at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to these alkaline phosphatases (e.g., SEQ ID NOs: 1 -24; for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • any polypeptide having at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%,
  • a sALP can optionally be glycosylated at any appropriate one or more amino acid residues.
  • an sALP can have at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any of the sALPs described herein (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • a sALP can have 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more additions, deletions, or substitutions relative to any of the sALPs described herein (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • TNALP for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • any of the sALPs (such as TNALP, for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa), linkers, spacers (e.g., Fc regions), and bone-targeting moieties described herein can be combined in a fusion polypeptide, which includes the structures Z-sALP-Y-spacer-X-W n -V, Z-Wn-X- spacer-Y-sALP-V, Z-sALP-Y-Wn-X-spacer-V, and Z-Wn-X-sALP-Y-spacer-V.
  • TNALP for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfo
  • the structure of the sALP fusion polypeptide can be Z-sALP-Y-spacer-X-Wn-V or Z-Wn-X-spacer-Y-sALP-V.
  • the sALP of the sALP fusion polypeptide can be the full-length ALP or functional fragments of ALPs, such as the soluble, extracellular domain of the ALP, as is described herein (e.g., TNALP, PALP, GCALP and IALP).
  • X, Y, Z, and V and/or the spacer can be absent or a linker region including an amino acid sequence of at least one amino acid.
  • X, Y, Z, and V may be a dipeptide sequence (e.g., leucine-lysine or aspartic acid-isoleucine), such as a two residue linker at the Y position (e.g., leucine-lysine) or a two residue linker at the X position (e.g., aspartic acid-isoleucine).
  • sALP fusion polypeptides can have the structure hTNALP-Fc-Dio (e.g., a sALP fusion polypeptide including the amino acid sequence of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa).
  • hTNALP-Fc-Dio e.g., a sALP fusion polypeptide including the amino acid sequence of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa.
  • the linker region can be of any sequence and length that allows the sALP to remain biologically active, e.g., not sterically hindered.
  • Exemplary linker lengths are between 1 and 200 amino acid residues, e.g., 1 -5, 6-10, 1 1 -15, 16-20, 21 -25, 26-30, 31 -35, 36-40, 41 -45, 46-50, 51 -55, 56-60, 61 -65, 66-70, 71 -75, 76-80, 81 -85, 86-90, 91 -95, 96-100, 1 01 -1 10, 1 1 1 1 -120, 121 -130, 131 -140, 141 -150, 151 - 160, 161 -170, 171 -180, 181 -190, or 191 -200 amino acid residues.
  • linkers include or consist of flexible portions, e.g., regions without significant fixed secondary or tertiary structure.
  • Exemplary flexible linkers are glycine-rich linkers, e.g., containing at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% glycine residues.
  • Linkers can also contain, e.g., serine residues.
  • the amino acid sequence of linkers consists only of glycine and serine residues.
  • a linker can optionally be glycosylated at any appropriate one or more amino acid residues.
  • a linker as described herein can include any other sequence or moiety, attached covalently or non-covalently.
  • the linker can also be absent, in which the spacer (e.g., the Fc region) and the sALP are fused together directly, with no intervening residues.
  • Useful spacers include, but are not limited to, polypeptides comprising a Fc region.
  • a sALP can be a fusion polypeptide including an Fc region of an immunoglobulin at the N-terminal or C- terminal domain.
  • An immunoglobulin molecule has a structure that is well known in the art. It includes two light chains (-23 kD each) and two heavy chains (-50-70 kD each) joined by inter-chain disulfide bonds. Immunoglobulins are readily cleaved proteolytically (e.g., by papain cleavage) into Fab
  • Fc fragments as described herein include the Fc fragment of any immunoglobulin molecule, including IgG, IgM, IgA, IgD, or IgE, and their various subclasses (e.g., lgG-1 , lgG-2, lgG-3, lgG-4, lgA-1 , lgA-2), from any mammal (e.g., human).
  • the Fc fragment is human lgG-1 .
  • the Fc fragments can include, for example, the CH2 and CH3 domains of the heavy chain and any portion of the hinge region.
  • the Fc region can optionally be glycosylated at any appropriate one or more amino acid residues known to those skilled in the art.
  • the Fc fragment of the fusion polypeptide has the amino acid sequence of SEQ ID NO: 20, or has at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 20.
  • Fc regions can be incorporated into the sALP fusion polypeptides described herein, e.g., those described in International Application Pub. No. WO2005/007809, which is hereby incorporated by reference.
  • An Fc fragment as described herein can have 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 1 8, 19, 20, 25, 30, 35, 40, 50, or more additions, deletions, or substitutions relative to any of the Fc fragments described herein.
  • D aspartate
  • E glutamate residues
  • the bone-targeting moiety if present, can be positioned anywhere in the fusion polypeptide, e.g., at or near the N-terminal or C-terminal end, and/or in the linker region.
  • the bone-targeting moiety can be present at the C-terminal end of a sALP fusion polypeptide.
  • sALPs and fusion polypeptides can also lack a bone-targeting moiety.
  • Additional amino acid residues can be introduced into the polypeptide according to the cloning strategy used to produce the fusion polypeptides. For instance, the additional amino acid residues do not provide an additional GPI anchoring signal so as to maintain the polypeptide in a soluble form.
  • any such additional amino acid residues when incorporated into the polypeptide of the methods, do not provide a cleavage site for endoproteases of the host cell.
  • the likelihood that a designed sequence would be cleaved by the endoproteases of the host cell can be predicted as described, e.g., by Ikezawa (Biol. Pharm. Bull. 25:409-417, 2002).
  • the sALP fusion polypeptides can be associated into dimers or tetramers.
  • a TNALP for example the sALP fusion polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • two sALP-Fc monomers can covalently be linked through two disulfide bonds located in the hinge regions of the Fc fragments.
  • the sALP fusion polypeptide e.g., a sALP or a sALP fusion polypeptide
  • nucleic acids encoding sALPs and sALP fusion polypeptides can be produced by any method known in the art.
  • a nucleic acid encoding the desired fusion polypeptide is generated using molecular cloning methods, and is generally placed within a vector, such as a plasmid or virus. The vector is used to transform the nucleic acid into a host cell appropriate for the expression of the fusion polypeptide.
  • Host cells can include, e.g., Chinese Hamster Ovary (CHO) cell, L cell, C127 cell, 3T3 cell, BHK cell, COS-7 cell or any other suitable host cell known in the art.
  • the host cell is a Chinese Hamster Ovary (CHO) cell (e.g., a CHO-DG44 cell).
  • the sALPs and sALP fusion polypeptides can be produced under any conditions suitable to effect expression of the sALP polypeptide in the host cell.
  • Such conditions include appropriate selection of a media prepared with components such as a buffer, bicarbonate and/or HEPES, ions like chloride, phosphate, calcium, sodium, potassium, magnesium, iron, carbon sources like simple sugars, amino acids, potentially lipids, nucleotides, vitamins and growth factors like insulin; regular commercially available media like alpha-MEM, DMEM, Ham's-F12, and IMDM supplemented with 2-4 mM L-glutamine and 5% Fetal bovine serum; regular commercially available animal protein free media like HycloneTM SFM4CHO, Sigma CHO DHFP , Cambrex POWERTM CHO CD supplemented with 2-4 mM L-glutamine.
  • These media are desirably prepared without thymidine, hypoxanthine and L-glycine to maintain selective pressure, allowing stable protein-product expression.
  • a composition that can be used in the methods described herein can be administered by a variety of methods known in the art.
  • a sALP or sALP fusion polypeptide such as TNALP
  • the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 e.g., asfotase alfa
  • the route and/or mode of administration will vary depending upon the desired results. The route of administration can depend on a variety of factors, such as the environment and therapeutic goals.
  • polypeptides and fusion polypeptides described herein can be administration by any route known in the art, e.g., subcutaneous (e.g., by subcutaneous injection), intravenously, orally, nasally, intramuscularly, sublingually, intrathecal ⁇ , or intradermally.
  • pharmaceutical compositions that can be used in the methods described herein can be in the form of a liquid, solution, suspension, pill, capsule, tablet, gelcap, powder, gel, ointment, cream, nebulae, mist, atomized vapor, aerosol, or phytosome.
  • any amount of a pharmaceutical composition e.g., including a sALP or sALP fusion polypeptide, such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a pharmaceutical composition can be administered to an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age).
  • the dosages will depend on many factors including the mode of administration and the age of the patient.
  • the amount of the composition e.g., a sALP or sALP fusion polypeptide, such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa
  • a condition e.g., HPP
  • the sALP polypeptides (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) described herein can be administered to an HPP patient, such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 1 8 years of age), in individual doses ranging, e.g., from 0.01 mg/kg to 500 mg/kg (e.g., from 0.05 mg/kg to 500 mg/kg, from 0.1 mg/kg to 20 mg/kg, from 5 mg/kg to 500 mg/kg, from 0.1 mg/kg to 100 mg/kg, from 10 mg/kg to 100 mg/kg, from 0.1 mg/kg to 50 mg/kg,
  • Exemplary doses of a sALP include, e.g., 0.01 , 0.05, 0.1 , 0.5, 1 , 2, 2.5, 5, 10, 20, 25, 50, 100, 125, 150, 200, 250, or 500 mg/kg; or 1 , 2, 2.5, 5, 10, 20, 25, 50, 100, 125, 150, 200, 250, 500, 750, 900, or 1 ,000 MQ/kg.
  • the term "about" can be used to modify these dosages by ⁇ 10% of the recited values or range endpoints.
  • compositions e.g., including sALP (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa)
  • sALP such as TNALP
  • a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 e.g., asfotase alfa
  • doses ranging from about 0.001 mg/kg/day to about 500 mg/kg/day, about 0.01 mg/kg/day to about 1 00 mg/kg/day, or about 0.01 mg/kg/day to about 20 mg/kg/day.
  • the sALP compositions can be administered to patients in a weekly dosage ranging, e.g., from about 0.5 mg/kg/week to about 140 mg/kg/week, e.g., about 0.8 mg/kg/week to about 50 mg/kg/week, or about 1 mg/kg/week to about 10 mg/kg/week (e.g., about 6 or about 9 mg/kg/week).
  • the sALP (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be administered at a dosage of 2 mg/kg three times a week (total dose 6 mg/kg/week), 1 mg/kg six times a week (total dose 6 mg/kg/week), 3 mg/kg three times a week (total dose 9 mg/kg/week), 0.5 mg/kg three times a week (total dose of 1 .5 mg/kg/week), or 9.3 mg/kg three times a week (total dose 28 mg/kg/week).
  • TNALP total dose 6 mg/kg/week
  • 1 mg/kg six times a week total dose 6 mg/kg/week
  • 3 mg/kg three times a week total dose 9 mg/kg/week
  • 0.5 mg/kg three times a week total
  • the dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from the HPP patient, such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 1 8 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age).
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 1 8 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age.
  • compositions including sALPs and sALP fusion polypeptides can be provided in either a single or multiple dosage regimens.
  • Doses can be administered, e.g., hourly, bihourly, daily, bidaily, twice a week, three times a week, four times a week, five times a week, six times a week, weekly, biweekly, monthly, bimonthly, or yearly.
  • doses can be administered, e.g., twice, three times, four times, five times, six times, seven times, eight times, nine times, 10 times, 1 1 times, or 12 times per day.
  • the dosing regimen is once weekly.
  • the duration of the dosing regimen can be, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 1 5, 16, 1 7, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 day(s), week(s), or month(s), or even for the remaining lifespan of the HPP patient, such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age).
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g
  • the amount, frequency, and duration of dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from the HPP patient, such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age).
  • an adolescent having HPP e.g., an adolescent having HPP of about 12 to about 18 years of age
  • an adult having HPP e.g., an adult having HPP older than about 18 years of age.
  • a sALP or sALP fusion polypeptide (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be formulated as a solution for injection, which is a clear, colorless to slightly yellow, aqueous solution, pH 7.4.
  • the sALP or sALP polypeptide may be formulated at a concentration of 12mg/0.3mL,18mg/0.45mL, 28mg/0.7mL, 40mg/1 ml, or 80mg/0.8mL.
  • the composition can be formulated as a 40 mg/ml solution for injection, in which each ml of solution contains 40 mg of sALP or sALP polypeptide (e.g., each vial contains 0.3 ml solution and 12 mg of sALP (40 mg/ml), each vial contains 0.45 ml solution and 1 8 mg of sALP (40 mg/ml), each vial contains 0.7 ml solution and 28 mg of sALP(40 mg/ml), or each vial contains 1 .0 ml solution and 40 mg of asfotase alfa (40 mg/ml)).
  • each vial contains 0.3 ml solution and 12 mg of sALP (40 mg/ml)
  • each vial contains 0.45 ml solution and 1 8 mg of sALP (40 mg/ml)
  • each vial contains 0.7 ml solution and 28 mg of sALP(40 mg/ml)
  • each vial contains 1 .0 ml
  • a sALP or sALP polypeptide (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be formulated as a solution for injection at a concentration of 100 mg/ml, in which each 1 ml of solution contains 100 mg of sALP or sALP polypeptide (e.g., each vial contains 0.8 ml solution and 80 mg of asfotase alfa (100 mg/ml)).
  • the recommended dosage of a sALP or sALP fusion polypeptide ((such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) is 2 mg/kg of body weight administered subcutaneously three times per week, or a dosage regimen of 1 mg/kg of body weight administered subcutaneously six times per week. Additional dosage information is provided below (Table 1 )-
  • compositions including sALPs and sALP fusion polypeptides can be formulated according to standard methods.
  • Pharmaceutical formulation is a well-established art, and is further described in, e.g., Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) Handbook of
  • a sALP composition (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8 °C (e.g., 4°C).
  • a composition can also be formulated for storage at a temperature below 0°C (e.g., -20°C or -8 n q C).
  • a composition can further be formulated for storage for up to 2 years (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 1 1 months, 1 year, 1 V2 years, or 2 years) at 2-8 °C (e.g., 4°C).
  • the compositions described herein can be stable in storage for at least 1 year at 2-8°C (e.g., 4 ⁇ €).
  • compositions including sALPs and sALP fusion polypeptides can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., injectable and infusible solutions
  • tablets, pills, powders, liposomes and suppositories e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends, in part, on the intended mode of administration and therapeutic application.
  • compositions intended for systemic or local delivery can be in the form of injectable or infusible solutions.
  • the compositions (such as TNALP, for example the sALP polypeptide of SEQ ID NO: 1 or a polypeptide variant having at least 95% sequence identity to the sequence of SEQ ID NO: 1 , e.g., asfotase alfa) can be formulated for administration by a parenteral mode (e.g., subcutaneous, intravenous, intraperitoneal, or intramuscular injection).
  • compositions including sALPs and sALP fusion polypeptides can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration.
  • Sterile injectable solutions can be prepared by incorporating a composition described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating a composition described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods for preparation include vacuum drying and freeze-drying that yield a powder of a composition described herein plus any additional desired ingredient (see below) from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition a reagent that delays absorption, for example, monostearate salts, and gelatin.
  • compositions described herein can also be formulated in immunoliposome compositions.
  • Such formulations can be prepared by methods known in the art such as, e.g., the methods described in Epstein et al. (1985) Proc Natl Acad Sci USA 82:3688; Hwang et al. (1980) Proc Natl Acad Sci USA 77:4030; and U.S. Patent Nos. 4,485,045 and 4,544,545.
  • Liposomes with enhanced circulation time are disclosed in, e.g., U.S. Patent No. 5,013,556.
  • compositions including sALPs and sALP fusion polypeptides can also be formulated with a carrier that will protect the composition (e.g., a sALP polypeptide or sALP fusion polypeptide) against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a carrier that will protect the composition (e.g., a sALP polypeptide or sALP fusion polypeptide) against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are known in the art. See, e.g., J.R. Robinson (1978) Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York.
  • compositions When compositions are to be used in combination with a second active agent, the compositions can be co-formulated with the second agent, or the compositions can be formulated separately from the second agent formulation.
  • the respective pharmaceutical compositions can be mixed, e.g., just prior to administration, and administered together or can be administered separately, e.g., at the same or different times.
  • Preparations containing a sALP or sALP fusion polypeptide can be provided to HPP patients, such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 1 8 years of age), in combination with pharmaceutically acceptable sterile aqueous or non-aqueous solvents, suspensions or emulsions.
  • HPP patients such as an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 1 8 years of age), in combination with pharmaceutically acceptable sterile aqueous or non-aqueous solvents, suspensions or emulsions.
  • nonaqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters.
  • Aqueous carriers include water, water-alcohol solutions, emulsions or suspensions, including saline and buffered medical parenteral vehicles including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium chloride solution, Ringer's solution containing lactose, or fixed oils.
  • the pharmaceutically acceptable carrier can include sodium chloride and/or sodium phosphate, in which the composition includes, e.g., about 150 mM sodium chloride and/or about 25 mM sodium phosphate, pH 7.4.
  • Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based upon Ringer's dextrose, and the like.
  • Pharmaceutically acceptable salts can be included therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances, and the like, can be present in such vehicles.
  • a thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991 ).
  • Adolescents and adults with hypophosphatasia of about 12 years to about 66 years of age participated in an initial phase study to determine the efficacy, safety, and tolerability of treatment with a soluble alkaline phosphatase (sALP) (asfotase alfa; SEQ ID NO: 1 ) for 6 months (Fig. 1 ).
  • sALP soluble alkaline phosphatase
  • the age of onset of HPP symptoms in the treatment group was less than 18 years of age for 10 patients, and was greater than or equal to about 18 years of age for 2 patients (Table 2).
  • the age of onset of HPP symptoms was unknown for 1 patient.
  • the age of onset of HPP symptoms in the control group was less than 18 years of age for 6 patients.
  • HPP patients selected for treatment with asfotase alfa had serum ALP below the age-adjusted normal range, plasma pyridoxal 5'-phosphate (PLP) concentrations of at least twice the upper normal limit, and evidence of osteopenia or osteomalacia in skeletal radiographs and/or bone biopsies.
  • Patients were excluded from the study for serum calcium or phosphate levels below the normal range, serum vitamin D levels less than 20 ng/mL, serum creatinine or parathyroid hormone levels above the upper limit of normal, or a medical condition or other extenuating circumstances that could significantly interfere with patient compliance with the study protocol.
  • HPP patient characteristics prior to treatment with asfotase alfa included fractures, bone pain, muscle complaints, joint complaints, unusual gait, and requiring assistive devices for mobility or ambulation (Table 3).
  • Table 3 Characteristics of HPP patients prior to treatment with asfotase alfa. Dosage treatment groups (2.1 mg/kg/week and 3.5 mg/kg/week) were combined for all results.
  • Asfotase alfa was administered via subcutaneous administration at an initial dose of 0.5 mg/kg/day (3.5 mg/kg/week), which was increased after 1 year to 1 mg/kg/day administered via subcutaneous administration once daily over 6 days (6 mg/kg/week).
  • the dosage of asfotase alfa was maintained at 6 mg/kg/week for the remainder of the extension phase.
  • 3 patients discontinued treatment with asfotase alfa due to injection site reactions (2 patients) and non-compliance with the treatment protocol (1 patient).
  • Metrics used during the extension phase to assess treatment of HPP with asfotase alfa included: 1 ) changes in inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) concentrations in patient plasma samples to assess ALP activity; 2) Six Minute Walk Test (6MWT) values to assess walking ability; and 3) Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) scores to assess physical function.
  • Example 2 Plasma inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) concentrations
  • ALP activity in plasma samples of the HPP patients was assessed by quantifying the
  • ALP substrates PPi and PLP concentrations of the ALP substrates PPi and PLP, as described in Whyte et al., 1 995 (J. Clin. Invest. 95(4): 1440-1445), hereby incorporated by reference in its entirety.
  • PPi and PLP concentrations in plasma samples from the control group and group treated with asfotase alfa were elevated at baseline from the normal range (Table 4).
  • ALP activity values were relatively low (23.5 U/L for the control group and 1 8.0 U/L for the treatment group) compared to age- and gender-adjusted ALP activity values (40 U/L to 160 U/L).
  • pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) concentrations prior to treatment with asfotase alfa were pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) concentrations prior to treatment with asfotase alfa.
  • plasma PPi and PLP concentrations were combined for the treatment group and control group at each respective time point (6 month, 1 year, 2 years, and 3 years of asfotase alfa treatment), since the control group received treatment with asfotase alfa after the initial phase of 6 months. Due to the 6 month offset in treatment with asfotase alfa of the control group, plasma PPi and PLP are not available for the control group patients at 4 years. Measurements of plasma PPi and PLP concentrations were combined for of all patients (treatment and control groups) at baseline (Fig. 2A).
  • the median plasma PPi concentration was 5.26 ⁇ (minimum plasma PPi concentration of 2.15 ⁇ ; maximum plasma PPi concentration of 8.2 ⁇ ), while the median plasma PLP concentration was 267.0 ng/ml (minimum plasma PLP concentration of 28.8 ng/ml; a maximum plasma PLP concentration of 1590.0 ng/ml).
  • Plasma PPi concentrations decreased after 6 months of treatment with asfotase alfa, as indicated by a median change from baseline of -2.19 for patients treated with asfotase alfa compared to a change of -0.18 for the control group (Fig. 2B).
  • plasma PLP concentrations decreased after 6 months of treatment with asfotase alfa, as indicated by a median change from baseline of -254.5 for patients treated with asfotase alfa compared to a change of -1 1 for the control group (Fig. 2B).
  • the decrease in plasma PPi concentrations was sustained throughout the extension phase of treatment with asfotase alfa (Fig. 2C).
  • the median plasma PPi concentration decreased to 3.39 ⁇ after 6 months of treatment with asfotase alfa (minimum plasma PPi concentration of 0.75 ⁇ ; maximum plasma PPi concentration of 6.00 ⁇ ).
  • the median PPi concentration was 3.94 ⁇ at 1 year (minimum plasma PPi concentration of 1 .62 ⁇ ; maximum plasma PPi concentration of 6.82 ⁇ ); the median PPi concentration was 2.63 ⁇ at 2 years (minimum plasma PPi concentration of 0.85 ⁇ ; maximum plasma PPi concentration of 10.90 ⁇ ); the median PPi concentration was 2.03 ⁇ at 3 years (minimum plasma PPi concentration of 1 .20 ⁇ ; maximum plasma PPi concentration of 4.58 ⁇ ); and the median PPi concentration was 2.56 ⁇ at 4 years (minimum plasma PPi concentration of 1 .09 ⁇ ; maximum plasma PPi concentration of 3.47 ⁇ ).
  • the decrease in plasma PLP concentrations was sustained throughout the extension phase of treatment with asfotase alfa (Fig. 2D).
  • the median plasma PLP concentration was 39.9 ng/ml after 6 months of treatment with asfotase alfa (minimum plasma PLP concentration of 2.5 ng/ml;
  • the median PLP concentration was 96.1 ng/ml at 1 year (minimum plasma PLP concentration of 6.3 ng/ml ; maximum plasma concentration of 367.0 ng/ml); the median PLP concentration was 21 .9 ng/ml at 2 years (minimum plasma PLP concentration of 2.7 ng/ml; maximum plasma PLP concentration of 192.0 ng/ml); the median PLP concentration was 14.1 ng/ml at 3 years (minimum plasma PLP concentration of 2.5 ng/ml; maximum plasma PLP concentration of 96.7 ng/ml); and the median PLP concentration was 12.5 ng/ml at 4 years (minimum plasma PLP concentration of 3.9 ng/ml; maximum plasma PLP concentration of 38.4 ng/ml).
  • 6MWT values were combined for the treatment group and control group at each respective time point (6 month, 1 year, 2 years, and 3 years of asfotase alfa treatment), since the control group received treatment with asfotase alfa after the initial phase of 6 months. Due to the 6 month offset in treatment with asfotase alfa of the control group, 6MWT values are not available for the control group patients at 4 years.
  • the increase in the 6MWT value was sustained throughout treatment with asfotase alfa at 81 .9% of the predicted 6MWT value (minimum predicted 6MWT value of 23.9%; maximum predicted 6MWT value of 121 .3%) after 1 year; 90.3% of the predicted 6MWT value (minimum predicted 6MWT value of 63.3%; maximum predicted 6MWT value of 120.8%) after 2 years; 91 .8% of the predicted 6MWT value (minimum predicted 6MWT value of 64.7%; maximum predicted 6MWT value of 121 .6%) after 3 years; and 84.4% of the predicted 6MWT value (minimum predicted 6MWT value of 59.0%; maximum predicted 6MWT value of 96.7%) after 4 years.
  • the 6MWT value of the patients having HPP treated with asfotase alfa improved from 76% of the predicted 6MWT value at baseline to 85% of the predicted 6MWT value, which is within the normal range of healthy subjects of the same age and height, by 6 months.
  • BOT-2 tests to assess running speed and agility of the HPP patients included the 50 foot shuttle run, sideways steps over balance beam, and one and two legged side hops (Fig. 4A).
  • BOT-2 tests to assess strength of the HPP patients included sit-ups, v-ups, standing long jump, wall sit, and push-ups (Fig. 4B).
  • BOT-2 speed and agility total scores and BOT-2 strength total scores were then determined from the sum of points awarded per BOT-2 tests for each time interval (baseline, 6 months, 1 year, 2 year, 3 years, and 4 years).
  • BOT-2 scores after baseline BOT-2 scores were combined for the treatment group and control group at each respective time point (6 month, 1 year, 2 years, and 3 years of asfotase alfa treatment), since the control group received treatment with asfotase alfa after the initial phase of 6 months. Due to the 6 month offset in treatment with asfotase alfa of the control group, BOT-2 scores are not available for the control group patients at 4 years.
  • Table 5 Occurrence of injection site reactions in patients treated with asfotase alfa for 4 years.
  • ISRs included 87 instances of erythema (58% of total patients); 59 instances of discoloration (37% of total patients); 20 instances of hematoma (37% of total patients); 23 instances of pain (32% of total patients); 8 instances of atrophy (26% of total patients); 20 instances of pruritus (26% of total patients); 34 instances of reactions (21 % of total patients); 12 instances of swelling (21 % of total patients); and 4 instances of induration (1 1 % of total patients).

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Abstract

L'invention concerne des méthodes de traitement de l'hypophosphatasie (HPP) chez un patient (par exemple un adolescent ou un adulte atteint de HPP) présentant des troubles physiques ou une capacité de marche réduite, par l'administration d'une phosphatase alcaline soluble (sALP) au patient.
PCT/US2017/025590 2016-04-01 2017-03-31 Méthodes de traitement de l'hypophosphatasie chez les adolescents et les adultes WO2017173395A1 (fr)

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